Japanese Journal of Clinical Oncology Advance Access originally published online on June 27, 2006
Japanese Journal of Clinical Oncology 2006 36(8):483-488; doi:10.1093/jjco/hyl055
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© 2006 Foundation for Promotion of Cancer Research
Glu346Lys Polymorphism in the Methyl-CpG Binding Domain 4 Gene and the Risk of Primary Lung Cancer
1 Department of Internal Medicine, 2 Cancer Research Institute and 3 Department of Preventive Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
For reprints and all correspondence: Jae Yong Park, Department of Internal Medicine, Kyungpook National University Hospital, Samduk 2Ga 50, Daegu, 700-412, South Korea. E-mail: jaeyong{at}knu.ac.kr
Received February 1, 2006; accepted April 15, 2006
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Abstract |
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 TOP Abstract INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Background: Methyl-CpG binding domain 4 (MBD4) protein functions as a DNA repair enzyme and minimizes mutations at 5-methylcytosine. Polymorphisms in the DNA repair gene MBD4 may be associated with differences in DNA repair capacity and thereby influence an individual's susceptibility to lung cancer. To test this hypothesis, we examined the potential association between the MBD4 Glu346Lys polymorphism and the risk of lung cancer in a Korean population.
Methods: The MBD4 Glu346Lys genotypes were determined in 432 lung cancer patients and 432 healthy age- and gender-matched control subjects.
Results: The distribution of the MBD4 Glu346Lys genotypes was not significantly different between the overall lung cancer cases and the controls. However, when the cases were categorized by tumor histology, the Lys346Lys genotype was associated with a significantly decreased risk of adenocarcinoma (AC) as compared with the Glu346Glu genotype [adjusted odds ratio (OR) = 0.50, 95% confidence interval (CI) = 0.26–0.97, P = 0.04]. On the stratification analysis, the protective effect of the Lys346Lys genotype against AC was statistically significant in older individuals and heavier smokers (adjusted OR = 0.08, 95% CI = 0.01–0.64, P = 0.02; and adjusted OR = 0.09, 95% CI = 0.01–0.72, P = 0.02, respectively).
Conclusions: Our findings suggest that the MBD4 Glu346Lys polymorphism could be used as a marker for genetic susceptibility to AC of the lung.
Key Words: MBD4 • polymorphism • genetic susceptibility • lung cancer
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INTRODUCTION |
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TOPAbstractINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Although cigarette smoking is the major cause of lung cancer, only a fraction of smokers develop lung cancer during their lifetime, and this suggests that genetic constitution is important in determining an individual's susceptibility to lung cancer (1,2). This genetic susceptibility may result from inherited polymorphisms in the genes that are involved in carcinogen metabolism and repair of DNA damage (3,4).
DNA cytosine methylation in CpG dinucleotides is a major epigenetic mechanism that regulates chromosomal stability and gene expression (5,6). Many human cancers, including lung cancer, have both global hypomethylation and regional hypermethylation of CpG islands (7–10). Such aberrant DNA methylation may contribute to carcinogenesis in several ways. Hypomethylation may lead to chromosomal instability, reactivation of transposable elements and loss of imprinting (8,11). De novo hypermethylation of promoter CpG islands may lead to silencing of tumor suppressor genes and DNA repair genes (6,8,11). Methylated CpG sequences may increase susceptibility to attack by some environmental carcinogens (12,13). Methylation of CpG sequences may facilitate C-to-T transitions in tumor suppressor genes and/or oncogenes through deamination of 5-methylcytosine to thymine (14).
Methylated CpG sites are recognized by a family of protein factors containing methyl-CpG binding domain (MBD); to date, five family members have been identified in mammals: MeCP2, MBD1, MBD2, MBD3 and MBD4 (15–17). Four of these proteins, MeCP2, MBD1, MBD2 and MBD3 play important roles for methylation-mediated transcriptional silencing by recruiting chromatin modifying factors, such as histone deacetylases, to the methylated promoters (16,17). In contrast to the other family members, MBD4 protein has a thymine glycosylase activity and it binds preferentially to 5mCpG-TpG mismatches, which are the primary products of deamination of methyl-CpG. Therefore, MBD4 protein is thought to function as a DNA repair enzyme that minimizes mutations at 5-methylcytosine (18–20). In addition to its role in the DNA repair, MBD4 also plays an important role in genomic surveillance and apoptosis by interacting with the mismatch repair/tumor suppressor protein hMLH1 and the Fas-associated death domain protein (21).
Single nucleotide polymorphisms are the most common form of human genetic variation, and they may contribute to the individual susceptibility for lung cancer. We previously demonstrated that some variants in the DNA repair genes affect either the expression or the activities of enzymes and therefore, they are associated with the risk of lung cancer (22–24). Thus, we hypothesized that functional polymorphisms in the MBD4 gene may have an impact on MBD4 expression or activity, and so they modulate the susceptibility to lung cancer. To test this hypothesis, a case–control study was conducted to evaluate the association between the MBD4 polymorphism and the risk of lung cancer. Among the MBD4 polymorphisms identified, this study focused on the Glu346Lys polymorphism (rs140693) because this polymorphism has been reported to be associated with the risk of esophageal squamous cell carcinoma even though the functional significance of this polymorphism remains to be investigated (25).
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MATERIALS AND METHODS |
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TOPAbstractINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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STUDY POPULATION
This case-control study included 582 lung cancer patients and 582 healthy controls. The method used for subject enrollment was the same as for our previous studies (26,27). In brief, the eligible cases included all the patients who were newly diagnosed with primary lung cancer between January 2001 and June 2002 at Kyungpook National University Hospital, Daegu, Korea. There were no age, gender, histological or stage restrictions, but patients with a prior history of cancers were excluded from this study. The cases included 270 (46.4%) squamous cell carcinomas (SCCs), 205 (35.2%) adenocarcinomas (ACs), 97 (16.7%) small cell carcinomas (SmCCs) and 10 (1.7%) large cell carcinomas. The demographics and clinical characteristics of the cases were consistent with those of a nationwide lung cancer survey conducted by the Korean Academy of Tuberculosis and Respiratory Disease in 1998 (28). The high prevalence of male and SCC in the study population might be due to the very high smoking rate among males (68.3%) and low smoking rate among females (6%) in Korea (28). The control subjects were randomly selected from a pool of healthy volunteers who visited the general health check-up center at Kyungpook National University Hospital during the same period. The control subjects were frequency matched (1:1) to the cancer cases based on gender and age (±5 years). All the cases and the controls were ethnic Koreans and they resided in Daegu City or the surrounding regions. A detailed questionnaire was completed for each patient and control by a trained interviewer. The questionnaire included information on the average number of cigarettes smoked daily and the number of years the subjects had been smoking. For smoking status, a person who had smoked at least once a day for >1 year in his or her lifetime was regarded as a smoker. A former-smoker was defined as one who had stopped smoking at least 1 year before either the diagnosis of lung cancer (cases) or the date the informed consent form had been signed (controls). Cumulative cigarette dose (pack-years) was calculated using the following formula: pack-years = (packs per day) x (years smoked).
MBD4 GENOTYPING
Genomic DNA was extracted from peripheral blood lymphocytes by proteinase K digestion and phenol/chloroform extraction. The MBD4 Glu346Lys genotype was determined using a PCR-RFLP assay. The PCR primers (GenBank accession no. NT_005612
[GenBank]
) for the MBD4 Glu346Lys polymorphism (35650605G>A) were 5'-GTATG GGCACGAATACAAGA-3' (forward) and 5'-CCAAAGACTCAGAACACAT(mutated A
T)C-3' (reverse), which generate a 265 bp fragment. The PCRs were performed in a total volume of 20 µl containing 100 ng genomic DNA, 25 pM of each primer, 0.2 mM dNTPs, 1 x PCR buffer [50 mM KCl and 10 mM Tris–HCl (pH 8.3)], 1.5 mM MgCl2 and 1 unit of Taq polymerase (Takara Shuzo Co., Otsu, Shiga, Japan). The PCR cycle conditions consisted of an initial denaturation step at 94°C for 5 min followed by 35 cycles of 30 s at 94°C; 30 s at 55°C; 30 s at 72°C and a final elongation at 72°C for 10 min. The PCR products were digested overnight with 5 units of aTaqI (New England BioLabs, Inc., Beverly, MA, USA) at 65°C. The digested PCR products were resolved on 6% acrylamide gel and stained with ethidium bromide for visualization under UV light. Genotyping analysis was performed "blind" with respect to the case/control status in order to ensure quality control. Approximately 10% of samples were randomly selected to be genotyped again by a different author, and the results showed 100% concordance. The genotyping results were confirmed by examining selected PCR-amplified DNA samples (n = 2, respectively, for each genotype) by DNA sequencing. The results were also 100% concordant.
STATISTICAL ANALYSIS
Cases and controls were compared using a Student's t-test for continuous variables and a 
2 test for categorical variables. The Hardy–Weinberg equilibrium was tested with a goodness-of-fit 2 test with one degree of freedom for comparing the observed genotype frequencies with the expected genotype frequencies among the subjects. Unconditional logistic regression analysis was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), with adjustment for the possible confounders (gender as a nominal variable; age and pack-years of smoking, as continuous variables). Multiple logistic regression analyses were performed to analyze the association between the genotypes and risk of lung cancer after stratification into age (median age), gender, smoking status, cigarette consumption (median pack-years) and histological types of lung cancer. All analyses were performed using Statistical Analysis Software for Windows, version 8.12 (SAS institute, Gary, NC, USA).
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RESULTS |
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TOPAbstractINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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PATIENT CHARACTERISTICS
The demographics of the cases and controls enrolled in this study are shown in Table 1. There were no significant differences between the cases and controls in mean age or gender distribution, suggesting that the matching based on these two variables was adequate. The case group had a higher prevalence of current-smokers than the controls (P < 0.001), and the number of pack-years in smokers was significantly higher in the cases than in the controls (40.0 ± 17.7 versus 34.1 ± 17.8 pack-years; P < 0.001). These differences were controlled for in the later multivariate analyses.
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ASSOCIATION BETWEEN MBD4 GENOTYPES AND THE RISK OF LUNG CANCER
The genotype and polymorphic 346Lys allele frequencies of the MBD4 Glu346Lys polymorphism among the controls and cases are shown in Table 2. The distribution of the genotypes among the controls was in the Hardy–Weinberg equilibrium. The frequencies of the Glu/Glu, Glu/Lys and Lys/Lys genotypes among the overall lung cancer cases (48.1, 43.1 and 8.8%, respectively) were not significantly different from those among the controls (44.2, 44.5 and 11.3%, respectively). When the cases were categorized by the tumor histology, the frequency of the Lys/Lys genotype among AC cases (5.9%) was significantly lower than that among the controls (11.3%; P = 0.02), and the Lys346Lys genotype was associated with a significantly decreased risk of AC compared with the Glu346Glu genotype (adjusted OR = 0.50, 95% CI = 0.26–0.97, P = 0.04). Adjusted ORs were similar to crude ORs. No significant association was found between the Glu346Lys genotypes and the risk of SCC or SmCC (Table 3).
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The association between the MBD4 Glu346Lys genotypes and the risk of AC was further examined after stratification according to gender, age and smoking status. Because the risk of lung cancer for the Glu346Lys genotype was similar to that of the Glu346Glu genotype, we combined the Glu346Lys genotype with the Glu346Glu genotype into one group and used it as the reference group. The risk estimates for the Lys346Lys genotype are presented in Table 4. When stratified by median age, a significant reduction in risk was observed in the older individuals (adjusted OR = 0.08, 95% CI = 0.01–0.64, P = 0.02), while there was no significant association in younger individuals (adjusted OR = 0.89, 95% CI = 0.43–1.84). When the ever-smokers were dichotomized by median pack-years of smoking, the Lys346Lys genotype was associated with a significantly decreased risk of AC in heavier-smokers (adjusted OR = 0.09, 95% CI = 0.01–0.72, P = 0.02), while there was no significant association in the lighter-smokers.
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DISCUSSION |
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TOPAbstractINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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This is the first study showing that the MBD4 Glu346Lys polymorphism is associated with a significantly decreased risk of AC of the lung. This finding suggests that this polymorphism could be used as a marker for genetic susceptibility to AC of the lung. Of three major histological types of lung cancer, the proportion of AC is increasing worldwide. Thus, identification of genetic factors that are responsible for susceptibility to AC is indispensable for establishing novel and efficient ways of preventing the disease.
An interesting finding of this study is that the MBD4 polymorphism had a more pronounced association with AC. Although the reasons for the observed histology-dependent difference in risk conferred by the MBD4 polymorphism are unclear, this difference might be due to differences in the pathways of carcinogenesis among the different histological types of lung cancer (29,30). Therefore, genetic factors involved in the susceptibility to cancer can differ according to the histological subtypes of lung cancer (31–35). In our previous studies (26,27), there was also a significant association between DNMT3B and MBD1 polymorphisms and the risk of AC. This suggests that genetic variants in the DNA methylation-related genes including DNMT3B, MBD1 and MBD4 might have a pronounced association with development of AC. Among the various carcinogens in tobacco smoke, tobacco-specific N-nitrosamines such as 4-(methylnitrosamino)-1-(pyridyl)-1-butanone (NNK) are known to be important causative agents for AC (29). DNA methylation is the critical pathway for NNK-induced lung tumorigenesis (36,37). Therefore, it is possible that genetic variants of the MBD4 gene, which are involved in the repair of methylated adducts of CpG sequences, play an important role in determining the genetic susceptibility to AC. On the other hand, SCC and SmCC have been linked to polyaromatic hydrocarbons such as benzo[a]pyrene (29). PAHs preferentially induce bulky helix-distorting adducts such as benzo[a]pyrene guanine adducts which result in G:C to T:A transversions. These bulky helix-distorting adducts formed by PAHs are mainly repaired through the nucleotide excision repair pathway (38). Hence, it is conceivable that polymorphisms in the MBD4 gene play only a minor role in determining the risk of SCC and SmCC. However, it is possible that these findings were due to chance because of the relatively small number of subjects in the subgroups, particularly in the SmCC group. Therefore, large studies will be needed to confirm this finding.
Several recent studies have shown that mutations in the kinase domain of the epidermal growth factor receptor gene, like the K-ras mutations, frequently target AC; but they are more frequent in never-smokers, females and the East Asian populations, while the K-ras mutations are more frequent in smokers, males and the Western populations (39,40). These observations suggest that ACs arising in the never-smokers and smokers may be caused by different etiologies relating to environmental risk factors and also genetic susceptibility factors (39–41). Therefore, we performed a stratification analysis to examine if the MBD4 genotypes may have differential effects on the risk of AC according to age, gender and the smoking status. In the present study, the MBD4 polymorphism had a more pronounced association with AC in heavier-smokers. However, because the number of subjects in the subgroups was small, our findings from the stratified analyses should be interpreted with caution before being confirmed in larger studies.
Hao et al. (25) reported that the MBD4 Lys346Lys genotype was associated with a 1.25-fold increased risk of esophageal SCC in a Chinese population. In contrast, in the present study, the Lys346Lys genotype was associated with a significantly decreased risk of lung AC. Although the reasons for the discrepant results between the previous and the present studies are unclear, it is possible that differences in the etiologies and target genes somatically altered during carcinogenesis between lung AC and esophageal SCC caused the different results. Therefore, the genetic susceptibility factors for lung AC might be different from those for esophageal SCC (25,42). Sakiyama et al. (42) recently reported that the MBD4 Glu346Lys polymorphism was not associated with the risk of lung cancer in a Japanese population. The different results in Japanese and Korean studies might be due to ethnic and environmental differences. There is increasing evidence of different impacts of genetic polymorphisms on the risk of lung cancer between Japanese and Koreans (24,42,43). However, given that the protective effect of the Lys346Lys genotype against AC was significant only in older individuals and heavier-smokers in the present study, it is possible that the difference in the results between the two studies may be due to the differences in the age and smoking status of the study subjects. In addition, inadequate study design such as non-random sampling, limited sample size and the pitfalls arising from unknown confounders also need be considered. The selection bias in a hospital-based case-control study might also be a relevant issue. Given that most lung cancer patients are treated at a University Hospital in Korea, it is reasonable to assume that the case group is representative of lung cancer cases in our community. Another selection bias might have been derived from the controls who did not participate in this study. However, self-selection bias is unlikely given that the age and gender distribution of the non-participating controls were similar to those of the participating control subjects in this study. The fact that the allele and genotype frequencies among the control subjects are consistent with those derived from the Hardy–Weinberg equilibrium further supports the non-biased sampling of our study. However, because the numbers of subjects in the subgroups were relatively small, larger studies will be needed to validate the genetic effect of the MBD4 polymorphism on lung cancer.
Whether the MBD4 Glu346Lys polymorphism itself affects MBD4 activity or is in linkage disequilibrium with other functional polymorphisms remains to be investigated. Although this polymorphism causes a neutral substitution not residing in any of the known functional domains, an amino acid change from acidic Glu to basic Lys could alter its interaction with damaged DNA. An alternative explanation for the association between the polymorphism and the risk of lung cancer may be due to linkage disequilibrium with either other MBD4 variants or with an adjacent true susceptible gene.
In this study, the frequency of the variant 346Lys allele among healthy controls was 0.336 and was similar to that (0.358) of cancer-free Chinese (25). The frequency of the 346Lys allele reported in the NIH Database (http://www.ncbi.nlm.nih.gov/SNP) ranges from 0.000 of African Americans to 0.311 of Native Americans and Hispanic, and it was 0.212 in 85 subjects from the Pacific Rim. Ethnic variation in the MBD4 polymorphism warrants additional studies to clarify the association of the MBD4 polymorphism with the risk of lung cancer in different ethnic populations.
In conclusion, we found that the MBD4 Glu346Lys polymorphism was significantly associated with the risk of lung cancer, and particularly AC. This finding suggests that the MBD4 gene may be involved in the development of lung cancer, although additional studies having larger sample sizes are required to confirm our findings. Future studies on the other MBD4 sequence variants and their biologic function are also needed to understand the role of the MBD4 polymorphism in determining the risk of lung cancer. Moreover, since genetic polymorphisms often vary between different ethnic groups, further studies are needed to clarify the association of the MBD1 polymorphism with lung cancer in different ethnic populations.
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Acknowledgments |
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This study was supported in part by the Grant No. RTI04-01-01, the Regional Technology Innovation Program of the Ministry of Commerce, Industry and Energy (MOCIE), Republic of Korea.
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References |
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1 Sellers TA, Bailey-Wilson JE, Potter JD, Rich SS, Rothschild H, Elston RC. Effect of cohort differences in smoking prevalence on models of lung cancer susceptibility. Genet Epidemiol 1992;9:261–71.[CrossRef][ISI][Medline]
2 Shields PG, Harris CC. Cancer risk and low-penetrance susceptibility genes in gene-environment interactions. J Clin Oncol 2000;18:2309–15.
3 Hecht SS. Cigarette smoking and lung cancer: chemical mechanisms and approaches to prevention. Lancet Oncol 2002;3:461–9.[CrossRef][ISI][Medline]
4 Spitz MR, Wei Q, Dong Q, Amos CI, Wu X. Genetic susceptibility to lung cancer: the role of DNA damage and repair. Cancer Epidemiol Biomark Prev 2003;12:689–98.
5 Jones PA, Laird PW. Cancer epigenetics comes of age. Nat Genet 1999;21:163–7.[CrossRef][ISI][Medline]
6 Baylin SB, Herman JG. DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet 2000;16:168–74.[CrossRef][ISI][Medline]
7 Gama-Sosa MA, Slagel VA, Trewyn RW, Oxenhandler R, Kuo KC, Gehrke CW, et al. The 5-methylcytosine content of DNA from human tumors. Nucleic Acids Res1983;11:6883–94.
8 Robertson KD. DNA methylation, methyltransferases, and cancer. Oncogene 2001; 20:3139–55.[CrossRef][ISI][Medline]
9 Woodson K, Mason J, Choi SW, Hartman T, Tangrea J, Virtamo J, et al. Hypomethylation of p53 in peripheral blood DNA is associated with the development of lung cancer. Cancer Epidemiol Biomark Prev 2001;10:69–74.
10 Zochbauer-Muller S, Fong KM, Virmani AK, Geradts J, Gazdar AF, Minna JD. Aberrant promoter methylation of multiple genes in non-small cell lung cancer. Cancer Res 2001;61:249–55.
11 Esteller M, Herman JG. Cancer as an epigenetic disease: DNA methylation and chromatic alterations in human cancers. J Pathol 2002;196:1–7.[CrossRef][ISI][Medline]
12 Denissenko MF, Chen JX, Tang MS, Pfeifer GP. Cytosine methylation determines hot spots of DNA damage in the human P53 gene. Proc Natl Acad Sci 1997;94:3893–8.
13 Yoon JH, Smith LE, Feng Z, Tang MS, Lee CS, Pfeifer GP. Methylated CpG dinucleotides are the preferential targets for G-to-T transversion mutations induced by benzo[a]pyrene diol epoxide in mammalian cells: similarities with the p53 mutation spectrum in smoking-associated lung cancers. Cancer Res 2001;61:7110–7.
14 Gonzalgo ML, Jones PA. Mutagenic and epigenetic effects of DNA methylation. Mutat Res 1997;386:107–18.[CrossRef][ISI][Medline]
15 Hendrich B, Bird A. Identification and characterization of a family of mammalian methyl-CpG binding proteins. Mol Cell Biol 1998;18:6538–549.
16 Wade PA. Methyl CpG-binding proteins: coupling chromatin architecture to gene regulation. Oncogene 2001;20:3166–73.[CrossRef][ISI][Medline]
17 Ballestar E, Wolffe AP. Methyl CpG binding proteins: targeting specific gene repression. Eur J Biochem 2001;268:1–6.[ISI][Medline]
18 Hendrich B, Hardeland U, Ng HH, Jiricny J, Bird A. The thymine glycosylase MBD4 can bind to the product of deamination at methylated CpG sites. Nature 1999; 401:301–4.[CrossRef][Medline]
19 Petronzelli F, Riccio A, Markham GD, Seeholzer SH, Stoerker J, Genuardi M, et al. Biphasic kinetics of the human DNA repair protein MED1 (MBD4), a mismatch-specific DNA N-glycosylase. J Biol Chem 2000;275:32422–9.
20 Petronzelli F, Riccio A, Markham GD, Seeholzer SH, Genuardi M, Karbowski M, et al. Investigation of the substrate spectrum of the human mismatch-specific DNA N-glycosylase MED1 (MBD4): fundamental role of the catalytic domain. J Cell Physiol 2000;185:473–80.[CrossRef][ISI][Medline]
21 Screaton RA, Kiessling S, Sansom OJ, Miller CB, Maddison K, Bird A, et al. Fas-associated death domain protein interacts with methyl-CpG binding domain protein 4, a potential link between genome surveillance and apoptosis. Proc Natl Acad Sci USA 2003;100:5211–6.
22 Park JY, Lee SY, Jeon HS, Bae NC, Chae SC, Joo S, et al. Polymorphism of the DNA repair gene XRCC1 and risk of primary lung cancer. Cancer Epidemiol Biomark Prev 2002;11:23–7.
23 Park JY, Park SH, Choi JE, Lee SY, Jeon HS, Cha SI, et al. Polymorphism of the DNA repair gene XPA and risk of primary lung cancer. Cancer Epidemiol Biomark Prev 2002; 11:993–7.
24 Lee GY, Jang J-S, Lee SY, Jeon HS, Kim KM, Choi JE, et al. XPC polymorphisms and lung cancer risk. Int J Cancer 2005;115:807–13.[CrossRef][ISI][Medline]
25 Hao B, Wang H, Zhou K, Li Y, Chen X, Zhou G, et al. Identification of genetic variants in base excision repair pathway and their association with risk of esophageal squamous cell carcinoma. Cancer Res 2004;64:4378–84.
26 Lee SJ, Jeon HS, Jang JS, Park SH, Lee GY, Lee BH, et al. DNMT3B polymorphisms and risk of primary lung cancer. Carcinogenesis 2004;26:403–9.
27 Jang JS, Lee SJ, Choi JE, Cha SI, Lee EB, Park TI, et al. Methyl-CpG binding domain 1 gene polymorphisms and risk of primary lung cancer. Cancer Epidemiol Biomark Prev 2005;14:2474–80.
28 Lee CT, Kang KH, Koh Y, Chang J, Chung HS, Park SK, et al. Characteristics of lung cancer in Korea, 1997. Lung Cancer 2000;30:15–22.[CrossRef][ISI][Medline]
29 Hecht SS. Cigarette smoking and lung cancer: Chemical mechanisms and approaches to prevention. Lancet Oncol 2002;2:461–9.
30 Sekido Y, Fong KM, Minna JD. Molecular genetics of lung cancer. Annu Rev Med 2003;54:73–87.[CrossRef][Medline]
31 Gu J, Spitz MR, Yang F, Wu X. Ethnic differences in poly(ADP-ribose) polymerase pseudogene genotype distribution and association with lung cancer risk. Carcinogenesis 1999;20:1465–9.
32 Fan R, Wu MT, Miller D, Wain JC, Kelsey KT, Wiencke JK, et al. The p53 codon 72 polymorphism and lung cancer risk. Cancer Epidemiol Biomark Prev 2000; 9:1037–42.
33 Li G, Wang LE, Chamberlain RM, Amos CI, Spitz MR, Wei Q. p73 G4C14-to-A4T14 polymorphism and risk of primary lung cancer. Cancer Res 2004;64:6836–6.
34 Sugimura H, Kohno T, Wakai K, Nagura K, Genka K, Igarashi H, et al. hOGG1 Ser326Cys polymorphism and lung cancer susceptibility. Cancer Epidemiol Biomark Prev 1999;8:669–74.
35 Sunaga N, Kohno T, Yanagitani N, Sugimura H, Kunitoh H, Tamura T, et al. Contribution of the NQQ1 and GSTT1 polymorphisms to lung adenocarcinoma susceptibility. Cancer Epidemiol Biomark Prev 2002;11:730–8.
36 Hecht SS. DNA adduct formation from tobacco-specific N-nitrosamines. Mut Res 1999;424:127–42.[ISI][Medline]
37 Cloutier JF, Drouin R, Weinfeld M, O'Connor TR, Castonguay A. Characterization and mapping of DNA damage induced by reactive metabolites of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) at nucleotide resolution in human genomic DNA. J Mol Biol 2001;313:539–57.[CrossRef][ISI][Medline]
38 Yu Z, Chen J, Ford BN, Brackley ME, Glickman BW. Human DNA repair systems: an overview. Environ Mol Mutagen 1999;33:3–20.[CrossRef][ISI][Medline]
39 Marchetti A, Martella C, Felicioni L, Barassi F, Salvatore S, Chella A, et al. EGFR mutations in non-small cell lung cancer: analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment. J Clin Oncol 2005;23:857–65.
40 Shigematsu H, Lin L, Takahashi T, Nomura M, Suzuki M, Wistuba II, et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 2005;97:339–46.
41 Gazdar AF, Shigematsu H, Herz J, Minna JD. Mutations and addiction to EGFR: the Achilles ‘heal’ of lung cancers? Trends Mol Med 2004;10:481–6.[CrossRef][ISI][Medline]
42 Sakiyam T, Kohno T, Mimaki S, Ohta T, Yanagitani N, Sobue T, et al. Association of amino acid substitution polymorphisms in DNA repair genes TP53, POLI, REV1 and LIG4 with lung cancer risk. Int J Cancer 2005;114:730–7.[CrossRef][ISI][Medline]
43 Park JY, Lee SY, Jeon HS, Bae NC, Chae SC, Joo S, et al. Polymorphisms of the DNA repair gene XRCC1 and risk of primary lung cancer. Cancer Epidemiol Biomark Prev 2002;11:23–7.
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